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Formylpeptide receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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The formylpeptide receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on the formylpeptide receptor family [25]) respond to exogenous ligands such as the bacterial product fMet-Leu-Phe (fMLF) and endogenous ligands such as lipoxin A4 (LXA4), 15-epi-lipoxin A4, annexin I (ANXA1, P04083) , cathepsin G (CTSG, P08311), amyloid β42, serum amyloid A and spinorphin, derived from β-haemoglobin (HBB, P68871). FPR1 also serves as a plague receptor for selective destruction of human immune cells by Y. pestis [23]. The FPR1/2 agonists 'compound 17b' and 'compound 43' have shown cardiac protective functions [10,24].
Receptors
Targets of relevance to immunopharmacology are highlighted in blue
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FPR1
C
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FPR2
C
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FPR3 C
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Further reading
* Key recommended reading is highlighted with an asterisk
* Dahlgren C, Gabl M, Holdfeldt A, Winther M, Forsman H. (2016) Basic characteristics of the neutrophil receptors that recognize formylated peptides, a danger-associated molecular pattern generated by bacteria and mitochondria. Biochem Pharmacol, 114: 22-39. [PMID:27131862]
* Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K, Rossi AG. (2015) The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation. Am J Pathol, 185 (5): 1172-1184. [PMID:25791526]
Gavins FN. (2010) Are formyl peptide receptors novel targets for therapeutic intervention in ischaemia-reperfusion injury?. Trends Pharmacol Sci, 31 (6): 266-76. [PMID:20483490]
* Krepel SA, Wang JM. (2019) Chemotactic Ligands that Activate G-Protein-Coupled Formylpeptide Receptors. Int J Mol Sci, 20 (14). [PMID:31336833]
Liberles SD, Horowitz LF, Kuang D, Contos JJ, Wilson KL, Siltberg-Liberles J, Liberles DA, Buck LB. (2009) Formyl peptide receptors are candidate chemosensory receptors in the vomeronasal organ. Proc Natl Acad Sci USA, 106 (24): 9842-7. [PMID:19497865]
* Perretti M, Godson C. (2020) Formyl peptide receptor type 2 agonists to kick-start resolution pharmacology. Br J Pharmacol, 177 (20): 4595-4600. [PMID:32954491]
* Yazid S, Norling LV, Flower RJ. (2012) Anti-inflammatory drugs, eicosanoids and the annexin A1/FPR2 anti-inflammatory system. Prostaglandins Other Lipid Mediat, 98 (3-4): 94-100. [PMID:22123264]
* Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM. (2009) International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev, 61 (2): 119-61. [PMID:19498085]
References
1. Bae YS, Lee HY, Jo EJ, Kim JI, Kang HK, Ye RD, Kwak JY, Ryu SH. (2004) Identification of peptides that antagonize formyl peptide receptor-like 1-mediated signaling. J Immunol, 173 (1): 607-14. [PMID:15210823]
2. Chen T, Xiong M, Zong X, Ge Y, Zhang H, Wang M, Won Han G, Yi C, Ma L, Ye RD et al.. (2020) Structural basis of ligand binding modes at the human formyl peptide receptor 2. Nat Commun, 11 (1): 1208. [PMID:32139677]
3. Clish CB, O'Brien JA, Gronert K, Stahl GL, Petasis NA, Serhan CN. (1999) Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo. Proc Natl Acad Sci USA, 96 (14): 8247-52. [PMID:10393980]
4. Cooray SN, Gobbetti T, Montero-Melendez T, McArthur S, Thompson D, Clark AJ, Flower RJ, Perretti M. (2013) Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc Natl Acad Sci USA, 110 (45): 18232-7. [PMID:24108355]
5. Fiore S, Maddox JF, Perez HD, Serhan CN. (1994) Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. J Exp Med, 180 (1): 253-60. [PMID:8006586]
6. Fiore S, Ryeom SW, Weller PF, Serhan CN. (1992) Lipoxin recognition sites. Specific binding of labeled lipoxin A4 with human neutrophils. J Biol Chem, 267 (23): 16168-76. [PMID:1322894]
7. Fiore S, Serhan CN. (1995) Lipoxin A4 receptor activation is distinct from that of the formyl peptide receptor in myeloid cells: inhibition of CD11/18 expression by lipoxin A4-lipoxin A4 receptor interaction. Biochemistry, 34 (51): 16678-86. [PMID:8527441]
8. Freer RJ, Day AR, Muthukumaraswamy N, Pinon D, Wu A, Showell HJ, Becker EL. (1982) Formyl peptide chemoattractants: a model of the receptor on rabbit neutrophils. Biochemistry, 21 (2): 257-63. [PMID:6280748]
9. Freer RJ, Day AR, Radding JA, Schiffmann E, Aswanikumar S, Showell HJ, Becker EL. (1980) Further studies on the structural requirements for synthetic peptide chemoattractants. Biochemistry, 19 (11): 2404-10. [PMID:7387981]
10. García RA, Ito BR, Lupisella JA, Carson NA, Hsu MY, Fernando G, Heroux M, Bouvier M, Dierks E, Kick EK et al.. (2019) Preservation of Post-Infarction Cardiac Structure and Function via Long-Term Oral Formyl Peptide Receptor Agonist Treatment. JACC Basic Transl Sci, 4 (8): 905-920. [PMID:31909300]
11. Ge Y, Zhang S, Wang J, Xia F, Wan JB, Lu J, Ye RD. (2020) Dual modulation of formyl peptide receptor 2 by aspirin-triggered lipoxin contributes to its anti-inflammatory activity. FASEB J, 34 (5): 6920-6933. [PMID:32239559]
12. Gronert K, Martinsson-Niskanen T, Ravasi S, Chiang N, Serhan CN. (2001) Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. Am J Pathol, 158 (1): 3-9. [PMID:11141472]
13. Guilford WJ, Bauman JG, Skuballa W, Bauer S, Wei GP, Davey D, Schaefer C, Mallari C, Terkelsen J, Tseng JL et al.. (2004) Novel 3-oxa lipoxin A4 analogues with enhanced chemical and metabolic stability have anti-inflammatory activity in vivo. J Med Chem, 47 (8): 2157-65. [PMID:15056011]
14. He HQ, Liao D, Wang ZG, Wang ZL, Zhou HC, Wang MW, Ye RD. (2013) Functional characterization of three mouse formyl peptide receptors. Mol Pharmacol, 83 (2): 389-98. [PMID:23160941]
15. Koo C, Lefkowitz RJ, Snyderman R. (1982) The oligopeptide chemotactic factor receptor on human polymorphonuclear leukocyte membranes exists in two affinity states. Biochem Biophys Res Commun, 106: 442-449. [PMID:6285921]
16. Krishnamoorthy S, Recchiuti A, Chiang N, Fredman G, Serhan CN. (2012) Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. Am J Pathol, 180 (5): 2018-27. [PMID:22449948]
17. Krishnamoorthy S, Recchiuti A, Chiang N, Yacoubian S, Lee CH, Yang R, Petasis NA, Serhan CN. (2010) Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci USA, 107 (4): 1660-5. [PMID:20080636]
18. Le Y, Murphy PM, Wang JM. (2002) Formyl-peptide receptors revisited. Trends Immunol, 23 (11): 541-8. [PMID:12401407]
19. Liang TS, Gao JL, Fatemi O, Lavigne M, Leto TL, Murphy PM. (2001) The endogenous opioid spinorphin blocks fMet-Leu-Phe-induced neutrophil chemotaxis by acting as a specific antagonist at the N-formylpeptide receptor subtype FPR. J Immunol, 167 (11): 6609-14. [PMID:11714831]
20. Maddox JF, Hachicha M, Takano T, Petasis NA, Fokin VV, Serhan CN. (1997) Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G-protein-linked lipoxin A4 receptor. J Biol Chem, 272 (11): 6972-8. [PMID:9054386]
21. Migeotte I, Riboldi E, Franssen JD, Grégoire F, Loison C, Wittamer V, Detheux M, Robberecht P, Costagliola S, Vassart G et al.. (2005) Identification and characterization of an endogenous chemotactic ligand specific for FPRL2. J Exp Med, 201 (1): 83-93. [PMID:15623572]
22. Murphy PM, Ozçelik T, Kenney RT, Tiffany HL, McDermott D, Francke U. (1992) A structural homologue of the N-formyl peptide receptor. Characterization and chromosome mapping of a peptide chemoattractant receptor family. J Biol Chem, 267 (11): 7637-43. [PMID:1373134]
23. Osei-Owusu P, Charlton TM, Kim HK, Missiakas D, Schneewind O. (2019) FPR1 is the plague receptor on host immune cells. Nature, 574 (7776): 57-62. [PMID:31534221]
24. Qin CX, May LT, Li R, Cao N, Rosli S, Deo M, Alexander AE, Horlock D, Bourke JE, Yang YH et al.. (2017) Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice. Nat Commun, 8: 14232. [PMID:28169296]
25. Qin CX, Norling LV, Vecchio EA, Brennan EP, May LT, Wootten D, Godson C, Perretti M, Ritchie RH. (2022) Formylpeptide receptor 2: Nomenclature, structure, signalling and translational perspectives: IUPHAR review 35. Br J Pharmacol, 179 (19): 4617-4639. [PMID:35797341]
26. Showell HJ, Freer RJ, Zigmond SH, Schiffmann E, Aswanikumar S, Corcoran B, Becker EL. (1976) The structure-activity relations of synthetic peptides as chemotactic factors and inducers of lysosomal secretion for neutrophils. J Exp Med, 143 (5): 1154-69. [PMID:1262785]
27. Stenfeldt AL, Karlsson J, Wennerås C, Bylund J, Fu H, Dahlgren C. (2007) Cyclosporin H, Boc-MLF and Boc-FLFLF are antagonists that preferentially inhibit activity triggered through the formyl peptide receptor. Inflammation, 30 (6): 224-9. [PMID:17687636]
28. Sun R, Iribarren P, Zhang N, Zhou Y, Gong W, Cho EH, Lockett S, Chertov O, Bednar F, Rogers TJ, Oppenheim JJ, Wang JM. (2004) Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor. J Immunology, 173: 428-436. [PMID:15210802]
29. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN. (1997) Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors. J Exp Med, 185 (9): 1693-704. [PMID:9151906]
30. Walther A, Riehemann K, Gerke V. (2000) A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR. Mol Cell, 5 (5): 831-40. [PMID:10882119]
31. Wenzel-Seifert K, Seifert R. (1993) Cyclosporin H is a potent and selective formyl peptide receptor antagonist. Comparison with N-t-butoxycarbonyl-L-phenylalanyl-L-leucyl-L-phenylalanyl-L- leucyl-L-phenylalanine and cyclosporins A, B, C, D, and E. J Immunol, 150 (10): 4591-9. [PMID:8387097]
32. Yan P, Nanamori M, Sun M, Zhou C, Cheng N, Li N, Zheng W, Xiao L, Xie X, Ye RD et al.. (2006) The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding. J Immunol, 177 (10): 7050-8. [PMID:17082621]
33. Zhang S, Gong H, Ge Y, Ye RD. (2020) Biased allosteric modulation of formyl peptide receptor 2 leads to distinct receptor conformational states for pro- and anti-inflammatory signaling. Pharmacol Res, 161: 105117. [PMID:32768626]
34. Zhuang Y, Liu H, Edward Zhou X, Kumar Verma R, de Waal PW, Jang W, Xu TH, Wang L, Meng X, Zhao G et al.. (2020) Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nat Commun, 11 (1): 885. [PMID:32060286]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Richard D. Ye (Chairperson)
François Boulay
Claes Dahlgren
Craig Gerard
Philip M. Murphy
Marc Parmentier
Mark Quinn
Charles N. Serhan
Ji Ming Wang |
Other contributors:
Magnus Bäck
Nan Chiang
Sven-Erik Dahlén
Jeffrey Drazen
Jilly F. Evans
G. Enrico Rovati
Takao Shimizu
Takehiko Yokomizo |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License
Note that the data for FPR2/ALX are also reproduced on the leukotriene receptor page.
FPR1 has been reported to be the plague receptor on host immune cells [23]. By interacting with LcrV, the needle cap protein of the type III secretion system of Y. pestis, FPR1 serves to promote translocation of virulent factors of the bacteria. The R190W mutation of FPR1 confers resistance to this function of Y. pestis. Several FPR1/2 agonists including 'compound 17b' and 'compound 43' have been shown to display cardiac protective functions in mouse models of myocardial ischemia-reperfusion injury [10,24]. Studies have been conducted to explore the mechanisms by which FPR2 mediates both inflammatory and anti-inflammatory signaling in a ligand-dependent manner. The status of FPR2 dimerization is a determining factor for ligand-specific conformational changes leading to biased signaling [4]. There is also a report on ligand concentration-dependent dual modulation of FPR2 by lipoxin A4 for receptor-activation vs. anti-inflammatory activities [11]. Some FPR2 ligands may display allosteric modulatory effects that cause changes in FPR2 conformational states and receptor signaling [33]. The 3-D structure of FPR2 has been solved by the use of cryo-electron microscopy [34] and receptor protein crystallization [2]. The FPR2 structure reveals a large binding pocket that can accommodate several ligands of different shapes and sizes.